Genome-wide association scans (GWAS) in human SLE have identified DNA segments that likely harbor causal variants, however, the precise identities of these variants have remained elusive. The primary objective of this "Grand Opportunity" proposal is to define, through the judicious application of state-of-the-art genomic technologies, a set of candidate causal genetic variants from GWAS defined SLE risk loci that justify the time and expense associated with molecular functional analysis. To do this we will leverage the progress of two large genomic studies currently underway in our laboratories, the Large Lupus Association Study 2 (LLAS2) and the SLE Sequence Capture and Deep Resequencing (SleqCap) project. LLAS2 is a collaborative study of 42 investigators who have contributed SNP hypotheses (33,787 total) and/or DNA samples (14,965 total) for genotyping in a multiethnic case/control cohort. SleqCap facilitates discovery of novel rare variants using custom designed sequence capture microarrays followed by massively parallel sequencing. Our proposal has three scientific aims. The objective of Aim 1 will be to expand the power and scope of the LLAS2 project through the addition of a complete set of Hispanic cases and controls and to thoroughly explore the utility of family-based genetic fine mapping approaches by genotyping affected siblings and unaffected family members in over 2000 pedigrees of European and African American descent. Resulting genotype data will be analyzed using a variety of methods to select the top candidates for resequencing in Aim 2. In Aim 2 our objectives will be to employ microarray-based sequence capture methods to isolate SLE associated genomic loci using a NimbleGen chip that we have designed and fully optimized. Isolated DNA segments from all four ethnic populations will be resequenced using massively parallel sequencing technology. Sequence data will be assembled and analyzed for common and uncommon variants using a combination of publically and commercially available sequence analysis tools. Experiments in Aim 3 will validate novel variants identified through resequencing by genotyping in subjects from all four ethnic groups. These data will be integrated into the master project database through imputation. We will then apply a customized bioinformatic method that incorporates variant specific information, such as whether a variant alters a protein coding sequence or regulatory motif, to produce a rank ordered list of candidate causal variants with high likelihood of conferring functional influence on SLE pathophysiology. We are confident that the integration and expansion of the LLAS2 and SleqCap projects as a result of "GO" funding will lead to significant and rapid advancements in our understanding of the genetic underpinnings of SLE. This will benefit not only those who suffer from SLE and related disorders but also the U.S. economy through the establishment and retention of 5 well-paying biotech jobs and the purchase of $3M in goods and services from U.S. companies.